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ETS2 is a prostate basal cell marker and is highly expressed in prostate cancers aberrantly expressing p63.

ABSTRACT: BACKGROUND:Rare prostate carcinomas aberrantly express p63 and have an immunophenotype intermediate between basal and luminal cells. Here, we performed gene expression profiling on p63-expressing prostatic carcinomas and compared them to usual-type adenocarcinoma. We identify ETS2 as highly expressed in p63-expressing prostatic carcinomas and benign prostate basal cells, with lower expression in luminal cells and primary usual-type adenocarcinomas. METHODS:A total of 8 p63-expressing prostate carcinomas at radical prostatectomy were compared to 358 usual-type adenocarcinomas by gene expression profiling performed on formalin fixed paraffin embedded tumor tissue using Affymetrix 1.0 ST microarrays. Correlation between differentially expressed genes and TP63 expression was performed in 5239 prostate adenocarcinomas available in the Decipher GRID. For validation, ETS2 in situ hybridization was performed on 19 p63-expressing prostate carcinomas and 30 usual-type adenocarcinomas arrayed on tissue microarrays (TMA). RESULTS:By gene expression, p63-expressing prostate carcinomas showed low cell cycle activity and low Decipher prognostic scores, but were predicted to have high Gleason grade compared to usual-type adenocarcinomas by gene expression signatures and morphology. Among the genes over-expressed in p63-expressing carcinoma relative to usual-type adenocarcinoma were known p63-regulated genes, along with ETS2, an ETS family member previously implicated as a prostate cancer tumor suppressor gene. Across several cohorts of prostate samples, ETS2 gene expression was correlated with TP63 expression and was significantly higher in benign prostate compared to usual-type adenocarcinoma. By in situ hybridization, ETS2 gene expression was high in benign basal cells, and low to undetectable in benign luminal cells or usual-type adenocarcinoma. In contrast, ETS2 was highly expressed in 95% (18/19) of p63-expressing prostate carcinomas. CONCLUSIONS:ETS2 is a predominantly basally-expressed gene in the prostate, with low expression in usual-type adenocarcinoma and high expression in p63-expressing carcinomas. Given this pattern, the significance of ETS2 loss by deletion or mutation in usual-type adenocarcinomas is uncertain.

SUBMITTER: Torres A

PROVIDER: S-EPMC6818503 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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ETS2 is a prostate basal cell marker and is highly expressed in prostate cancers aberrantly expressing p63.

Torres Alba A Alshalalfa Mohammed M Davicioni Elai E Gupta Anuj A Yegnasubramanian Srinivasan S Wheelan Sarah J SJ Epstein Jonathan I JI De Marzo Angelo M AM Lotan Tamara L TL

The Prostate 20180515 12

<h4>Background</h4>Rare prostate carcinomas aberrantly express p63 and have an immunophenotype intermediate between basal and luminal cells. Here, we performed gene expression profiling on p63-expressing prostatic carcinomas and compared them to usual-type adenocarcinoma. We identify ETS2 as highly expressed in p63-expressing prostatic carcinomas and benign prostate basal cells, with lower expression in luminal cells and primary usual-type adenocarcinomas.<h4>Methods</h4>A total of 8 p63-express ...[more]

PMID: 29761525

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Project description:BackgroundMethylation plays a key role in the aetiology and pathogenesis of prostate cancer (PCa). This study aimed to identify aberrantly methylated differentially expressed genes (DEGs) and pathways in PCa and explore the underlying mechanisms of tumourigenesis.MethodsExpression profile (GSE29079) and methylation profile (GSE76938) datasets were obtained from the Gene Expression Omnibus (GEO). We used R 3.4.4 software to assess aberrantly methylated DEGs. The Cancer Genome Atlas (TCGA) RNA sequencing and Illumina HumanMethylation450 DNA methylation data were utilized to validate screened genes. Functional enrichment analysis of the screened genes was performed, and a protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Gens (STRING). The results were visualized in Cytoscape. After confirmation using TCGA, cBioPortal was used to examine alterations in genes of interest. Then, protein localization in PCa cells was observed using immunohistochemistry.ResultsOverall, 536 hypomethylated upregulated genes were identified that were enriched in biological processes such as negative regulation of transcription, osteoblast differentiation, intracellular signal transduction, and the Wnt signalling pathway. Pathway enrichment showed significant changes in factors involved in AMPK signalling, cancer, and adherens junction pathways. The hub oncogenes were AKT1, PRDM10, and FASN. Additionally, 322 hypermethylated downregulated genes were identified that demonstrated enrichment in biological processes including positive regulation of the MAPK cascade, muscle contraction, ageing, and signal transduction. Pathway analysis indicated enrichment in arrhythmogenic right ventricular cardiomyopathy (ARVC), focal adhesion, dilated cardiomyopathy, and PI3K-AKT signalling. The hub tumour suppressor gene was FLNA. Immunohistochemistry showed that AKT1, FASN, and FLNA were mainly expressed in PCa cell cytoplasm, while PRDM10 was mainly expressed in nuclei.ConclusionsOur results identify numerous novel genetic and epigenetic regulatory networks and offer molecular evidence crucial to understanding the pathogenesis of PCa. Aberrantly methylated hub genes, including AKT1, PRDM10, FASN, and FLNA, can be used as biomarkers for accurate PCa diagnosis and treatment. In conclusion, our study suggests that AKT1, PRDM10, and FASN may be tumour promoters and that FLNA may be a tumour suppressor in PCa. We hope these findings will draw more attention to these hub genes in future cancer studies.

Dataset Information

ETS2 is a prostate basal cell marker and is highly expressed in prostate cancers aberrantly expressing p63.

Publications

ETS2 is a prostate basal cell marker and is highly expressed in prostate cancers aberrantly expressing p63.

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